The inflammatory response is an attempt by the body to restore and maintain tissue structure and function after injury and is an integral part of body defense. Most of the body defense elements are located in the blood and inflammation is the means by which body defense cells and defense chemicals leave the blood and enter the tissue around the injured or infected site. Although inflammation is essentially a beneficial process, excessive or prolonged inflammatory activity can result in severe pain as well as having deleterious effects on tissues.
Sinomenine, a morphine-like alkaloid derived from sinomenum acutum, was reported to possess anti-inflammatory, antalgic, lowering blood pressure and anti-arrhythmia activities [Wang, Naiqin, et al. Yao Xue Xue Bao 1992, 23(2), 81; Zhou, Jinhuang et al. <<Zhongyao Yaoli Yanjiu Yu Jinzhan>>, Chinese Science and Technology Publisher, 1993, 66; Liu, Q.; Zhou, L.-l.; Li, R. Chinese Traditional and Herbal Drugs 1997, 28, 247.]. Sinomenine and its hydrochloride salt have been clinically used for the treatment of rheumatoid arthritis (RA) in China. However, it suffers from a slow onset of effect and some side-effects such as tetter etc.1 Some studies aimed at modification of sinomenine were concentrated on the reduction of the carbonyl group and hydrogenation of the double bond in the C-ring2, while other modification was concentrated on sinomenine-metal chelate (Pang, zhigong; Wang, Baoqi. Faming Zhuanli Shenqing Gongkai Shuomingshu (1997), CN 1153171. Chem. Abstr. 131:356078. Kang, Jun; Xue, Chunxia; Dong, Yaling. Xibei Yaoxue Zhazhi 2000, 16 (4), 137.), however there has been little success yet achieved to enhance sinomenine activity.
Beside the above described biological activities, some new uses of sinomenine and its derivatives, such as mnemocognition-facilitating have been found in animal experimental models (Qin Guo-Wei, et al. PCT Int. Appl. (2004), WO 2004/048340, Chem. Abstr. 131:179808).
New derivatives of sinomenine have been conceived and implemented using a distinct approach to modifying sinomenine. Specifically, by focusing on the substitutions of the methyl group on the D-ring, derivatives were identified that enhance the biological activity of the parent sinomenine. It cannot be ruled out that the derivatives' mode of action differs from the parent compound. In sum, provided herein are numerous 17-substituted derivatives and variants of sinomenine that have improved anti-inflammation bioactivities.